SAT053 Development Of A Novel Peptide-based Insulin Sensitizer Through Disruption Of Inositol Polyphosphate 5-Phosphatase K (SKIP) - p21-activated Kinase 1 (Pak1) Interactions
Disclosure: A.M. Kimbrough: None. J. Dev Gaddameedi: None. A.M. Lipchik: None. Type 2 diabetes (T2D) is a prominent, chronic metabolic disease that affects approximately 462 million people worldwide. The driving force behind T2D is insulin resistance (IR), defined as an impaired biological response...
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| Published in: | Journal of the Endocrine Society Vol. 7; no. Supplement_1 |
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| Main Authors: | , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
US
Oxford University Press
05-10-2023
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Disclosure: A.M. Kimbrough: None. J. Dev Gaddameedi: None. A.M. Lipchik: None.
Type 2 diabetes (T2D) is a prominent, chronic metabolic disease that affects approximately 462 million people worldwide. The driving force behind T2D is insulin resistance (IR), defined as an impaired biological response to insulin, and leads to a multitude of more severe conditions including heart disease, stroke, and neuropathy. Most therapies fail to improve insulin sensitivity, and instead drive physiological compensation. It is imperative to develop new therapies to correct the underlying pathology by targeting mechanisms of IR. Inositol polyphosphate 5-phosphatase K (INPP5K/SKIP) is a potential target to treat IR. SKIP resides in the endoplasmic reticulum (ER) in resting cells, and translocates to the plasma membrane (PM) following growth factor stimulation. SKIP is recruited to the PM through binding to p21 activated kinase 1 (Pak1) and inhibits growth factor signaling through dephosphorylation of phosphoinositol-(3,4,5)-triphosphate. In obesity and IR, SKIP is overexpressed leading to PM localization and suppression of insulin signaling. Here, we developed a novel insulin sensitizer utilizing a peptide derived from Pak1 to inhibit SKIP-Pak1 interactions and prevent PM localization. We found that the Pak1 derived peptide displayed alpha helical properties and thermostabilized SKIP. In controlled in vitro assays, the Pak1 peptide was successfully taken up in target tissues. Additionally, treatment with the Pak1 peptides was sufficient to restore insulin sensitivity in skeletal muscle, adipose, and liver models of IR. Together these results demonstrate the use of a peptide-based insulin sensitizer as a novel therapeutic for T2D that requires further investigation.
Presentation: Saturday, June 17, 2023 |
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| ISSN: | 2472-1972 2472-1972 |
| DOI: | 10.1210/jendso/bvad114.921 |